1. Field of the Invention
The invention relates to a method for determining chemical states of living animal or human tissue using nuclear magnetic resonance with a homogeneous constant magnetic field, the tissue being measured by means of a nuclear magnetic resonance measurement and the measured values obtained then being evaluated by comparison with measured values from reference measurements on comparable tissue to assess whether the chemical state of the tissue corresponds to a chemical normal state or to a deviating abnormal end state.
The invention also relates to an apparatus for determining chemical states of living animal or human tissue using nuclear magnetic resonance, comprising a high resolution nuclear magnetic resonance spectrometer for carrying out a nuclear magnetic resonance measurement on the tissue, means for determining measured values for the nuclear magnetic resonance measurement on the tissue, means for storing reference values for measurements on comparable tissue and means for comparing the measured values from the actual measurement and the reference measurement.
2. Description of the Prior Art
A method of this type and an apparatus of this type are disclosed in U.S. Pat. No. 3,789,832.
In the case of the known method, the tissue is placed in a homogeneous constant magnetic field and is then measured by means of a nuclear magnetic resonance measurement (relaxation time measurement). With this method the tissue can be measured as a tissue sample in vitro, or in vivo, in which case the entire human or animal body is introduced into the homogeneous constant magnetic field.
During the measurement, the magnetic resonance of the protons of the total water in the tissue is measured. This method is based on the knowledge that, starting from a normal state, which corresponds to a healthy state of the tissue, the degree of association of such water molecules, which are associated with protein chains in the cell membranes, can change to an abnormal end state deviating from said normal state, this change being detectable via a nuclear magnetic resonance measurement. The abnormal end state corresponds to that of a malignant tumor. If measured values are now available for the corresponding tissues in both states, that is to say the normal state and the abnormal end state, it is possible, from a comparison of these measured values with the measured values of the tissue actually measured, to make an allocation, that is to say to determine in which of the two states the tissue was at the time of the measurement.
A disadvantage of a method of this type and an apparatus of this type is that it is possible to make only a yes/no statement, i.e. whether the tissue is in the one or the other state. The statement that the tissue is in the abnormal end state with coarse morphological changes can also be furnished in a simpler manner by conventional histological methods and provides no information with regard to chemical processes or intermediate states. If the association of the water molecules with the protein chains in the cell membranes has changed to such an extent that this is detectable by the said nuclear magnetic resonance measurements, then there is already a tumor in a developed state, i.e. a proliferation penetrating into other cells with the formation of metastases. In this advanced state, a medical treatment of the tissue is possible only with difficulty and usually is not successful. It is true that it is possible to make certain statements with regard to the severity of the malignancy from the measurements made in accordance with the method mentioned initially, but the prerequisite for this is that a malignant tumor is already present, i.e. the statement with respect to the abnormal end state can at best be differentiated to indicate to what extent this state is advanced within the tissue sample measured.
A further disadvantage of the method mentioned initially is that the change in the extent of the association of the water molecules with the proteins of the cell membrane must manifest itself, i.e. that the measured change can be detected only as a consequence of a tumor growth. Other chemical changes, which take place earlier or are even a possible cause of the subsequent development of a malignant tumor, are not detected.
The document EP-A2-0 234 524 discloses a method with which, on the basis of nuclear magnetic resonance measurements on liquid samples, for example blood plasma, serum or the like, resonance lines in the resulting spectrum are selected which are associated with chemical substances other than water and which are compared with corresponding characteristic lines in reference spectra which correspond to the deviating abnormal chemical state in which these substances are likewise present. In the case of the comparison method, the half-width values (line width in the spectrum at half the height of a line) are used and protons of various classes of lipoproteins can be assigned to the selected lines. The "Fossel indices" derived therefrom are, it is true, numerical values which are manageable in practice, but which enable only a yes/no statement with regard to normal state or malignant end state and which at best enable a differentiation with regard to the degree of the malignancy of the end state reached. Lipoproteins can also be found in the case of chemical changes in the blood which are not to be ascribed to a malignant tumor. Furthermore, for it to be possible to determine a malignant end state of a tissue, this end state must already be very far advanced, in order to draw reliable statements from the plasma, which statements are also made more difficult because other atypical frequencies can be observed in the selected frequency range in the plasma (in this context see G. N. Chmurny et al., "A NMR Blood Test for Cancer: a Critical Assessment", NMR in Biomedicine, Vol. 1, No. 3, 1988).
By means of high resolution nuclear magnetic resonance measurements, proteolipids can be used both in one-dimensional and in two-dimensional (2D-COSY=two-dimensional scalar correlated spectroscopy) spectra to determine the chemical state of tissue. L. C. Wright et al., "A proteolipid in cancer cells is the origin of their high-resolution NMR spectrum", FEBS letters, Vol. 203, No. 2, pp. 164-168 (1986).
In the case of the method known from this publication also, the proteolipids are determined in the plasma and at best permit a conclusion to be drawn with respect to a serious malignant end state of the tissue. It is true that is has become known from this that, by means of high resolution nuclear magnetic resonance measurements, certain substances which are characteristic for the chemical end state can possibly already be determined at a time at which conventional histological methods are not yet able to do this, but this procedure likewise permits only the statement that this end state, that is to say the malignant state of the tissue, already exists.
Further studies have supported the abovementioned findings, that is to say that by means of high resolution nuclear magnetic resonance measurements the chemical end states of tissue, which correspond to malignant states, can possibly be recognised at a considerably earlier time than is possible using conventional histological methods (C. E. Mountford et al. "Classification of Human Tumours by High-Resolution Magnetic Resonance Spectroscopy", THE LANCET, Vol. 1, Mar. 22, 1986, pp. 651-653). It is again a disadvantage of this procedure is that at best the chemical end state can be recognised at an earlier time, but this end state must likewise already exist.
Further studies have shown that nuclei other than protons, that is to say, for example, phosphorus or fluorine nuclei, can also be used in nuclear magnetic resonance measurements for the determination of the chemical state of tissue, this being possible in the case of human and animal body tissues of various types. (C. E. Mountford et al., "NMR Analysis of Cancer Cells" Progress in Clinical Biochemistry and Medicine, 1986, Vol. 3, pp. 73-112).
It is a common disadvantage of all of the above-mentioned methods and apparatuses that they enable only a statement to be made with regard to whether a specific chemical end state already exists, it being possible at best to make a differentiation with respect to the extent to which this chemical state is already advanced in the tissue.